The Clinical And Biological Significance Of Tyrosine Kinases In Gastric Cancer

Keywords

Anticancer drugs; Biological functions; Clinical outcomes; Clinical trials; Gastric cancer; Receptor tyrosine kinase; Tumorigenesis; Tyrosine kinase; Tyrosine kinase inhibitors

Abstract

Gastric cancer (GC) is the leading cause of cancer-related mortality, and its deadly nature can be secondary to its presentation in advanced stages. Unavailability of any gold-standard treatment and also the lack of unanimous classification schemes that can lead to inter-observer variability, lead to difficulties in the clinical reproducibility. Several classification systems have been proposed for GC. The most used classification system is Lauren classification, which classifies it into “intestinal,” “diffuse,” and “mixed” subtypes. This chapter summarizes the characterization of GC with genomic and molecular analysis to stratify the heterogeneous disease, role of tyrosine kinase (TK), receptor tyrosine kinases (RTK) and tyrosine kinase inhibitors (TKI), targeted therapies and ongoing clinical trials, toxicities associated with various commonly used agents/regimens in the disease, and future perspective of TKI in GC. Advances in the genomic technologies have facilitated the study of key genetic alterations in GC including gene expression, epigenetic disturbances, chromosomal alterations, and transcriptional changes, which therefore can stratify GC at the molecular levels. The characterization of GC at molecular levels has led in developing new therapeutic targets that would potentially provide personalized prognosis and treatment. The RTKs are membrane-bound proteins that play significant role(s) in the pathogenesis of many cancers including GC. Of many RTKs, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) have been found with higher frequencies in metastatic growth and progression of GC, which serve as potential target(s) for targeted therapies in GC. Human epidermal growth factor receptor 2 (HER-2) that promotes cell proliferation, adhesion, migration, and differentiation is overexpressed in 15–30% of GC cases. The phase III ToGA (trastuzumab for gastric cancer) study evaluated the role of adding trastuzumab, an anti-HER-2 monoclonal antibody, to the chemotherapy regimen in the first line of treatment in patients with HER-2-positive advanced-stage GC. VEGF is seen to be overexpressed in up to 58% of GC cases. The REGARD study and the phase III study have shown an improved overall survival benefit with ramucirumab, a monoclonal VEGFR2 antibody. Cetuximab is used when EGFR is overexpressed in gastric tumors, and dovinitib decreased phosphorylation of FGFR2. Common toxicities of trastuzumab include fever, chills, hypotension, dyspnea, bronchospasm, and respiratory distress, but life-threatening side effects such as cardiotoxicity and congestive heart failure can also occur. In the RAINBOW trial, ramucirumab plus paclitaxel showed higher rates of neutropenia, and other toxicities related to ramucirumab included hypertension, thromboembolic disease, and hemorrhage. Cetuximab use can lead to skin disorders such as dry skin, dermatitis acneiform/rash, and paronychia. Taken together, these molecular and cellular mechanisms/targets and supporting clinical trials outcomes have a significant impact on the overall quality of life and the prognosis of patients with gastric cancer.

Publication Date

1-1-2018

Publication Title

Role of Tyrosine Kinases in Gastrointestinal Malignancies

Number of Pages

29-56

Document Type

Article; Book Chapter

Personal Identifier

scopus

DOI Link

https://doi.org/10.1007/978-981-13-1486-5_3

Socpus ID

85063457603 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85063457603

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